6-amino-3-pyridinesulfonamides

ABSTRACT

New 6-anilino-3-pyridinesulfonamides, e.g. those of the formula   THE N-oxide and salts thereof, are antiinflammatory agents.

United States Patent Mizzoni et al.

[ 1 June 20, 1972 [54] 6-AMINO-3-PYRIDINESULFONAMIDES [72] Inventors: Renal Herbert Mlzzonl, Long Valley R.D.; Herbert Morton Blotter, Summit. both of [73] Assignee: Abl-Gelgy Corporation, Summit, NJ.

[22] Filed: April 1, 1970 [21] Appl. No.: 24,869

Naegeli et a1., Chem. Abstracts (1), Vol. 33, pp. 1733- 1734, (1939).

Naegeli, Chem. Abstracts (11), Vol. 34, pp. 1 134, 1940). Dohrn et aL, Chem. Abstracts, Vol. 41, pp. 4809- 4811, (1947).

Primary Evaminer-Alan L. Rotman Attorney-Harry Goldsmith, Joseph G. Kolodny and Mario A. Monaco [5 7] ABSTRACT New 6-ani1ino-3-pyridinesulfonamides, e.g. those of the formula R= H alkyl, free, esterified or etherified OH, CF

N 0,, amino, free or functionally converted carboxy or sulfo R H, alkyl or acyl H or alkyl Am= an amino or hydrazine group m= 1-3 N 1 or 2 the N-oxide and salts thereof, are antiinflammatory agents.

4 Claims, No Drawings 6-AMINO-3-PYRIDINESULFONAMIDES SUMMARY OF THE INVENTION The present invention concerns and has for its object the provision of new 6-anilino-3-pyridinesulfonamides and pharmaceutically useful derivatives thereof, preferably of those corresponding to Formula I R H, alkyl, free, esterified or etherified OH, CF,,

amino, free or functionally converted carboxy or sulfo R H, alkyl or acyl R H or alkyl Am= an amino or hydrazino group N 1 or 2 DESCRlPTlON OF THE PREFERRED EMBODIMENTS The phenyl radical Ph is unsubstituted or substituted by one or more than one, preferably by up to three, advantageously one or two, of the same or different substituents selected from the group consisting of lower alkyl, e.g. methyl, ethyl, nor ipropyl or -butyl, free, etherified or esterified hydroxy, such as lower alkoxy, e.g. methoxy, ethoxy, nor i-propoxy or -butoxy, lower alkanoyloxy, e.g. acetoxy or propionyloxy, halogeno, e.g. fluoro, chloro or bromo, trifluoromethyl, nitro, amino, monoor di-lower alkylamino or lower alkyleneimino, e.g. monoor dimethylamino or -ethylamino, pyrrolidino or piperidino, free, esterified or amidated carboxy or sulfo, such as lower carbalkoxy or alkoxysulfonyl, carbamoyl, sulfamoyl, monoor di-lower alkylcarbarnoyl or -sulfamoyl, e.g. carbomethoxy, carbethoxy, methoxysulfonyl, monoor dimethylcarbamoyl or -sulfamoyl. The term lower, referred to above and hereinafter in connection with organic radicals or compounds respectively, defines such with up to seven, preferably up to four, carbon atoms.

Preferred Ph radicals are phenyl, monoor di-(lower alkyl)- phenyl, monoor di-(lower alkoxy)-phenyl, monoor di- (halogen )-phenyl, (halogeno, lower alkyl)-phenyl, (halogeno, trifluoromethyl)-phenyl, monoor bis-(trifluoromethyl)- phenyl, (di-lower alkylamino)-phenyl, (carboxy)-phenyl, (lower carbalkoxy)-phenyl or (sulfamoyl)-phenyl.

The alkyl radicals R,, R and R are preferably such with up to four carbon atoms, e.g. those mentioned above, especially methyl.

An acyl radical R, is preferably lower alkanoyl or alkenoyl, e.g. acetyl, propionyl, pivaloyl, acryloyl or methacryloyl, or Ph-lower alkanoyl or -alkenoyl, e.g. benzoyl, phenylacetyl or cinnamoyl.

The amino group Am is a primary, secondary or tertiary amino group, such as monoor di-lower alkylamino or lower alkyleneimino, e.g. such mentioned above. A hydrazino group Am is also unsubstituted or lower alkylated, e.g. mono-, dior trimethylhydrazino.

Salts of the primary or secondary amides are preferably those of therapeutically useful inorganic or organic bases, primarily the alkali metal or alkanine earth metal, e.g. sodium,

potassium, magnesium or calcium salts. The basic compounds also form acid addition salts, preferably such of therapeutically useful inorganic or organic acids, for example, those of strong metalloidic acids, such as hydrohalic, e.g. hydrochloric or hydrobromic; sulfuric, phosphoric, nitric or perchloric acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic embonic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halogenbenzenesulfonic, toluenesulfonic, naphthalenesulfonic or sulfanilic acid; methionine; tryptophane, lysine or arginine.

The compounds of the invention exhibit valuable pharmacological properties, primarily antiinflammatory effects. This can be demonstrated in animal tests using, for example mammals, such as rats as test objects. The compounds of the invention can be administered enterally, parenterally or topically, for example orally in the form of aqueous solutions or suspensions by stomach tube. The oral dosage may range between about 0.1 and mg/kg/day, preferably between about 0.5 and 50 mg/kg/day, advantageously between about 1 and 25 mg/kg/day. Thus, the compounds of the invention cause, for example, in the rat paw edema test [Winter et al, Proc Soc. Exp. Biol. Med. 111, 544 (1962)] an inhibition of the paw edema induced by carrageenin. Accordingly, the compounds of the invention are useful antiphlogistics. They are also useful intermediates in the preparation of other valuable products, primarily of pharmacologically active compounds.

Preferred are those compounds of Formula I in which Ph is phenyl, monoor di(lower alkyl)-phenyl, monoor di-(lower alkoxy)-phenyl, monoor di-(halogeno)-phenyl, (halogeno, lower alkyl)-phenyl, (halogeno, trifluoromethyl)-phenyl, monoor bis-(trifluoromethyl)-phenyl, (di-lower alkylamino)- phenyl, (carboxy)- phenyl, (lower carbalkoxy)-phenyl or (sulfamoyl)-phenyl, R, is hydrogen, lower alkyl or alkanoyl, each of R and R is hydrogen or lower alkyl, and Am is amino, monoor di-lower alkylamino or five to seven ring-membered lower alkyleneimino, or the alkali or alkaline earth metal salts of the compounds in which Am is amino or lower alkylamino or therapeutically useful acid addition salts thereof.

Especially valuable are the compounds of Formula I in which Ph is phenyl, monoor dimethylphenyl, monoor dimethoxyphenyl, monoor dichlorophenyl, (chloro, methyl)- phenyl, (chloro, trifluoromethyl)-phenyl, monoor bistrifluoromethylphenyl, dimethylaminophenyl, carboxyphenyl, carbethoxyphenyl or sulfamoylphenyl, each of R,, R and R is hydrogen or methyl and Am is amino, monoor dimethylamino, the sodium or potassium salt of the compounds in which Am is amino or methylamino or therapeutically useful acid addition salts thereof.

Outstanding are compounds of Formula I, where Ph is phenyl, monoor dimethylphenyl, chlorophenyl or trifluoromethylphenyl, each of R, and R is hydrogen, R is hydrogen or methyl and Am is amino.

The compounds of the invention are prepared according to methods in themselves known. Advantageously they are obtained by a. converting in a compound of the Formula ll in which X is a group capable of being converted into the amino group R,-NPh, or a salt thereof, X into said amino group or b) converting in a compound of Formula ill wherein Y is a group capable of being converted into the amino group Am, or a salt thereof, Y into said amino group and, if desired, converting any resulting compound into another compound of the invention.

The groups X or Y are, for example, a free or preferably a reactively etherified or esterified hydroxy group, such as lower alkoxy or, above all, halogeno, e.g. such mentioned above, advantageously chlorine, or X is also a nitro group.

The above-mentioned starting material is advantageously reacted with the amine R,-NHPH or H-Am respectively, wherein R, is hydrogen or. lower alkyl, preferably in the absence, but also in the presence of diluents, advantageously of such which are inert to the reagents and are solvents thereof, of catalysts, condensing agents and/or inert atmospheres, at low temperatures, room temperature or advantageously elevated temperatures, at atmospheric or superatmospheric pressure.

In the above reaction the amine reagent is advantageously used in excess, in order to neutralize any generated said. It may, however, also be used in equivalent amounts and in the presence of other condensing agents such as inorganic or organic bases, e.g. alkali metal carbonates or bicarbonates or tertiary nitrogen bases, for example tri-lower alkylamines, N,N-dimethyl-aniline or pyridine. I

The compounds of the invention so obtained may be converted into each other according'to known methods. For example, resulting compounds in which R, stands for hydrogen, may be reacted with a reactive ester of a corresponding alcohol, for example that of a hydrohalic or sulfonic acid or with a reactive functional derivative of a corresponding acid, such as a halide or anhydride thereof, e.g. acetyl chloride or acetic anhydride. Resulting acyl derivatives may be hydrolyzed, for example with the use of mild acidic or alkaline hydrolyzing agents, which prevent hydrolysis of the sulfonamide group. Resulting acidic compounds can be salified in the usual manner, i.e. by reaction with corresponding inorganic or organic bases, e.g. alkali metal or alkaline earth metal hydroxides or carbonates, or corresponding ion exchange preparations. Resulting bases can also be converted into acid addition salts by reacting them with the corresponding free acids, e.g. those mentioned above, or acidic ion exchange preparations.

These or other salts, for example, the picrates, can also be used for purification of the bases obtained; the bases are converted into salts, the salts are separated and the bases are liberated from the salts. in view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such, is possible or appropriate under the circumstances. Resulting mixtures of isomers can be separated into the single isomers by methods in themselves known, e.g. by fractional distillation, crystallization and/or chromatography.

The invention further includes any variant of the present process in which an intermediate product obtainable at any stage of the process is used as starting material and any remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts. Mainly those starting materials should be used in the reactions of the invention that lead to the formation of those compounds indicated above as being especially valuable.

The starting material is known or, if new, may be prepared according to the methods illustrated in the examples herein. Compounds of Formula Ill wherein Y is hydroxy or lower alkoxy, as well as the ammonium. metal or acid addition salts thereof are new and are considered as additional subject matter of the present invention. They are prepared analogous to reaction (a) from the corresponding pyridine-3-sulfonic acids, their esters or salts.

The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions containing an effective amount thereof in conjunction or admixture with excipients suitable for either enteral, parenteral or topical application. Preferred are tablets and gelatin cap sules comprising the active ingredient together with (a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, (b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt polyethyleneglycol, for tablets also (c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, if desired, (d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, enzymes of the binders or effervescent mixtures and/or (e) adsorbents, colorants, flavors and sweeteners. lnjectable compositions are preferably aqueous isotonic solutions or suspensions, and ointments or suppositories are advantageously fatty emulsions or suspensions. They may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solutions promoters, salts for regulating the osmotic pressure and/or buffers. They may also contain other therapeutically valuable substances. Said pharmaceutical compositions are prepared according to conventional mixing, granulating or coating methods respectively and contain about 0.1 to percent, preferably about 1 to 50 percent of the active ingredient.

The following examples illustrating the invention are not to be construed as being limitations thereon. Temperatures are given in degrees Centigrade and all parts wherever given are parts by weight.

EXAMPLE l The mixture of 3.75 g 6-chloro-3-pyridinesulfonamide and 38 ml 3-trifluoromethylaniline is stirred for 12 hours at under nitrogen. After cooling, it is filtered and the residue recrystallized from ethanol-hexane, to yield the 6-(3- trifluoromethylphenylamino)-3-pyridinesulfonamide of the formula V SO2 Hz C a" NH-- N/ melting at l76-l 78.

EXAMPLE 2 The mixture of 8.5 g 6-chloro-5-methyl-3-pyridinesulfonamide and 30 ml 3-trifluoromethylaniline is stirred under nitrogen for l8 hours at 130 and 4 hours at After cooling, the mixture is diluted with diethyl ether, filtered and the residue recrystallized from ethanol-hexane, to yield the 5- methyl-6-( 3-trifluoromethylphenylamino)-3-pyridinesulfonamide of the formula 1 cooling, the pH thereof is adjusted to 6.8 with sodium bicarbonate and the mixture evaporated in vacuo. The residue is and/or I taken up in hot dimethylfonnamide, the solution filtered, the filtrate concentrated in vacuo and the concentrate diluted withdiethyl ether. The precipitate formed is filtered off, washed with diethyl ether and dissolved in hot 95 percent aqueous ethanol. The solution is filtered, the filtrate evaporated and the residue recrystallized from dimethylsulfoxide isopropanol and ethanol, to yield the sodium 6-hydroxy-5-methyl-3-pyridinesulfonate melting above 300.

The mixture of 33.7 g thereof, 56.5 g phosphorous pentachloride and 35 ml phosphorus oxychloride is refluxed for 16 hours while stirring. After cooling, the mixture is poured into ice, the precipitate formed after one-half hour filtrated off, washed with water, dried and sublimated in vacuo, to yield the 6-chloro-5-methyl-3-pyridinesulfonyl chloride melting at 56-57.

To the solution of l 1.3 g thereof in 100 ml acetone, the mixture of 20 ml concentrated aqueous ammonia and 20 ml acetone is added dropwise during 1 hour while stirring at -30. After 4 hours the mixture is allowed to warm to room temperature, filtered and the residue washed with acetone. The filtrate is refiltered, evaporated and the residue recrystallized from isopropanol, to yield the 6-chloro-5-methyl-3- pyridinesulfonamide, melting at 192193.

EXAMPLE 3 EXAMPLE 4 Preparation of 10,00 tablets each containing 100.00 mg 0 the active ingredient:

Formula:

o-( 3-lriiluommcthylphcnylnmino)- .1-pyridincsull'omlmitlc lactose Corn starch 125.00 g Polyethylene glycol 6,000 150.00g Talcum powder 150.00 g Magnesium stearate 40.00 g Purified water q.s. 8.5

Procedure:

All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 65 ml water and the suspension added to the boiling solution of the polyethylene glycol in 260 ml water. The paste formed, is added to the powders which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35, broken on a screen with 1.2 mm openings and compressed into tablets using concave punches with 10.3 mm diameter, uppers bisected.

We claim:

1. A 6-anilino-3-pyridinesulfonamide of the formula SOzAm 1 wherein Ph is monoor di(lower alkoxy)-phenyl, monoor di- (halogeno )-phenyl, (halogeno, lower alkyl )-phenyl, (halogeno, trifluoromethyl)-phenyl, monoor bis- (trifluoromethy1)-phenyl, (di-lower alkylamino)-phenyl, R, is hydrogen or lower alkyl, each of R and R is hydrogen or lower alkyl and Am is an amino, monoor di-lower alkylamino or five or seven ring-membered lower alkyleneimino, or the alkali or alkaline earth metal salts of the compounds in which Am is amino or lower alkylamino or pharmaceutically useful acid addition salts thereof.

2. A compound as claimed in claim 1, in which formula Ph is monoor di-methoxyphenyl, monoor dichlorophenyl, (chloro, methyl)-phenyl, (chloro, trifluoromethyl)-pheny1, monoor bis-trifluoromethylphenyl, dimethylaminophenyl,

each of R R and R is hydrogen or methyl and Am is amino, monoor dimethylamino, the sodium or potassium salt of the compounds in which Am is amino or methylamino or therapeutically useful acid addition salts thereof.

3. A compound as claimed in claim 1, in which formula Ph is chlorophenyl or trifluoromethylphenyl, each of R and R is hydrogen, R is hydrogen or methyl and Am is amino.

4. A compound as claimed in claim 1, and being the 6-(3- trifluoromethylphenylamino)-3-pyridinesulfonamide. 

2. A compound as claimed in claim 1, in which formula Ph is mono- or di-methoxyphenyl, mono- or dichlorophenyl, (chloro, methyl)-phenyl, (chloro, trifluoromethyl)-phenyl, mono- or bis-trifluoromethylphenyl, dimethylaminophenyl, each of R1, R2 and R3 is hydrogen or methyl and Am is amino, mono- or dimethylamino, the sodium or potassium salt of the compounds in which Am is amino or methylamino or therapeutically useful acid addition salts thereof.
 3. A compound as claimed in claim 1, in which formula Ph is chlorophenyl or trifluoromethylphenyl, each of R1 and R3 is hydrogen, R2 is hydrogen or methyl and Am is amino.
 4. A compound as claimed in claim 1, and being the 6-(3-trifluoromethylphenylamino)-3-pyridinesulfonamide. 